In chronic spontaneous urticaria soluble FcεRI is elevated and linked to atopy and chronic inducible urticaria

To the Editor, Chronic Spontaneous Urticaria (CSU) is caused by the activation of skin mast cells (MCs) by various signals including IgG and IgE autoantibodies in autoimmune (type IIb) and autoallergic CSU, respectively. Tests for autoallergic CSU are needed but not available for routine clinical use. Elevated total IgE has been proposed as a biomarker, but study results are inconsistent and total IgE levels in autoallergic CSU may be elevated due to comorbid sensitization rather than the presence of pathogenetically relevant IgE autoantibodies. Upon IgE‐mediated activation, MCs release the soluble isoform of the high affinity IgE receptor (sFcɛRI), which results in increased serum levels. Serum sFcɛRI levels have been demonstrated to be elevated and linked to disease activity in patients with IgE‐driven allergies, and they are easy to implement in routine clinical practice with commercially available assays. The use of serum sFcεRI in classical allergies has been demonstrated to provide useful information on the clinical relevance of IgE sensitization. Whether or not sFcɛRI levels are elevated in patients with CSU, linked to their total IgE, and associated with clinical features of their disease is currently unknown. To address this, we measured sFcεRI levels retrospectively in the sera of 290 CSU patients and 29 healthy non‐atopic controls (HCs; Table E1 and Online Repository). Patients with CSU had significantly higher sFcεRI serum levels (median � IQR: 1.9 � 62.9 ng/mL) than HCs (1 � 0.1 ng/mL, p < 0.0001; Figure 1A). Half of the CSU patients (47%, 135/290) but only 10% (3/29) of HCs had elevated sFcεRI levels (>2 ng/mL; Table E1). We used the previously established cut‐off for sFcεRI (2 ng/mL) because it defined clinically relevant IgE‐sensitization in an allergic cohort. Total IgE levels (Figure 1B) were also significantly higher in CSU patients (93 � 1401 IU/mL) than HCs (21 � 379 IU/mL, p < 0.0001) and significantly correlated with sFcεRI levels, albeit weakly (r = 0.176, p < 0.005). Chronic Spontaneous Urticaria patients with normal and elevated IgE (>40 IU/mL) versus low IgE (<40 IU/mL) had significantly higher sFcεRI levels (p < 0.005; Figure 1C). Vice versa, patients with elevated versus normal sFcɛRI levels had more IgE (104 � 1401 vs. 90� 655 IU/mL; p = 0.05; Table 1 and Figure E1G). Virtually all serum s was IgE‐bound (r = 0.974, p < 0.0001; Figure E1A). sFcɛRI levels in CSU patients were not linked to age or gender, disease duration or activity, angioedema, or ASST (Figure E1 and Table 1), but were significantly higher in those with comorbid atopy (p < 0.05) or chronic inducible urticaria (CIndU, p < 0.05; Online Repository, Figure 1D,F). Vice versa, rates of comorbid atopy and CIndU were higher in patients with elevated sFcεRI levels (p < 0.01; Table 1). There was a trend toward lower sFcɛRI levels in type IIb CSU patients (Figure 1E) defined as triple positivity of autologous serum skin test, basophil tests and presence of IgG autoantibodies by immunoassay (Online Repository). Patients with features of type IIb (triple positive test) or part‐type IIb (at least one positive test) autoimmune CSU were analyzed in the previously reported PURIST study. Our study, the first on sFcɛRI in CSU, demonstrates that sFcɛRI is elevated in CSU and linked to total IgE and comorbidities. This supports the idea that IgE is a major driver of MC degranulation in CSU, where patients have IgE autoantibodies, for example, IgE to thyroid peroxidase, rather than relevant IgE to allergens. About half of the CSU patients have IgE autoantibodies, similar to the rate of patients with elevated sFcɛRI in our study. Based on our findings, we hypothesize that sFcɛRI may be a suitable marker for autoallergic CSU since it is solely released upon IgE‐mediated crosslinking, that is, in patients with relevant IgE sensitization. This retrospective analysis has several limitations and further research is ongoing to address the many questions raised by our findings. sFcɛRI levels need to be assessed and compared in CSU patients with and without IgE autoantibodies, and human skin MCs should be investigated for their release of sFcɛRI following activation by IgE versus IgG autoantibodies. Our findings strongly suggest, but do not prove, that sFcɛRI is a biomarker for autoallergic CSU. As such, it may aid individualized treatment in routine clinical practice.


In chronic spontaneous urticaria soluble FcεRI is elevated and linked to atopy and chronic inducible urticaria
To the Editor, Chronic Spontaneous Urticaria (CSU) is caused by the activation of skin mast cells (MCs) by various signals including IgG and IgE autoantibodies in autoimmune (type IIb) and autoallergic CSU, respectively. 1,2 Tests for autoallergic CSU are needed but not available for routine clinical use. Elevated total IgE has been proposed as a biomarker, but study results are inconsistent 3,4 and total IgE levels in autoallergic CSU may be elevated due to comorbid sensitization rather than the presence of pathogenetically relevant IgE autoantibodies.
Upon IgE-mediated activation, MCs release the soluble isoform of the high affinity IgE receptor (sFcɛRI), which results in increased serum levels. 5 Serum sFcɛRI levels have been demonstrated to be elevated and linked to disease activity in patients with IgE-driven allergies, [6][7][8] and they are easy to implement in routine clinical practice with commercially available assays. The use of serum sFcεRI in classical allergies has been demonstrated to provide useful information on the clinical relevance of IgE sensitization. Whether or not sFcɛRI levels are elevated in patients with CSU, linked to their total IgE, and associated with clinical features of their disease is currently unknown. To address this, we measured sFcεRI levels retrospectively in the sera of 290 CSU patients and 29 healthy non-atopic controls (HCs ; Table E1 and Online Repository).
There was a trend toward lower sFcɛRI levels in type IIb CSU patients ( Figure 1E) defined as triple positivity of autologous serum skin test, basophil tests and presence of IgG autoantibodies by immunoassay (Online Repository). Patients with features of type IIb (triple positive test) or part-type IIb (at least one positive test) autoimmune CSU were analyzed in the previously reported PURIST study. 9 Our study, the first on sFcɛRI in CSU, demonstrates that sFcɛRI is elevated in CSU and linked to total IgE and comorbidities. This supports the idea that IgE is a major driver of MC degranulation in CSU, where patients have IgE autoantibodies, for example, IgE to thyroid peroxidase, rather than relevant IgE to allergens. About half of the CSU patients have IgE autoantibodies, similar to the rate of patients with elevated sFcɛRI in our study. Based on our findings, we hypothesize that sFcɛRI may be a suitable marker for autoallergic CSU since it is solely released upon IgE-mediated crosslinking, that is, in patients with relevant IgE sensitization.
This retrospective analysis has several limitations and further research is ongoing to address the many questions raised by our findings. sFcɛRI levels need to be assessed and compared in CSU patients with and without IgE autoantibodies, and human skin MCs should be investigated for their release of sFcɛRI following activation by IgE versus IgG autoantibodies. Our findings strongly suggest, but do not prove, that sFcɛRI is a biomarker for autoallergic CSU. As such, it may aid individualized treatment in routine clinical practice.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. F I G U R E 1 Comparison of serum sFcɛRI (A) and total IgE (B) levels in Chronic Spontaneous Urticaria (CSU) patients and HCs. Serum sFcɛRI levels were compared in CSU patients with low (<40 IU/mL) and normal plus elevated (>40 IU/mL) total IgE levels (C) with and without comorbid atopy (D), endotypes (non-, part-and type IIb, E) or concomitant CIndU (F). Bars represent the median and error bars represent IQR. Mann-Whitney test was performed; *p < 0.05, **p < 0.01 and ***p < 0.001. CIndU: chronic inducible urticaria; CSU: chronic spontaneous urticaria; HC: healthy controls; IQR: interquartile range.  Chi-2 analysis where p < 0.05 was considered significant.

AUTHOR CONTRIBUTIONS
LETTER